A19-144, A2-73 and certain anticholinesterase inhibitor compositions and method for anti-seizure therapy

ABSTRACT

This invention concerns a dosage form comprising a therapeutically effective amount of A19-144 or A2-73 and a therapeutically effective amount of at least one AED. This invention further encompasses a method of treating a subject in need of such treatment comprising administering a therapeutically effective amount of A19-144 or A2-73 in conjunction with an therapeutically effective amount of an AED.

FIELD OF THE INVENTION

This invention concerns a dosage form comprising a therapeuticallyeffective amount of A19-144, alone and in combination with at least oneanti-epilepsy drug (AED) in a therapeutically effective anti-seizureamount. Particular reference is made to seizures arising from epilepsy.This invention further concerns a dosage form comprising atherapeutically effective amount of A2-73, alone and in combination withat least one anti-epilepsy drug (AED) in a therapeutically effectiveanti-seizure amount.

BACKGROUND

1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride(ANAVEXI19-144, or A19-144) is a compound which is believed to bind tomuscarinic acetylcholine and sigma-1 receptors with affinities in thelow micromolar range. It has been reported that A19-144 showedneuroprotective potential against amyloid toxicity in mice. Anavex 2-73(also termed A2-73) has a systematic name1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanaminehydrochloride and displays similar activity.

In particular, A19-144 has been reported as attenuating oxidativestress, caspases induction, cellular loss and learning and memorydeficits observed in mice one week after the icy injection of anoligomeric preparation of amyloid β₂₅₋₃₅ peptide (Aβ₂₅₋₃₅) (Villard etal., J Psychopharmacol 2011). More recently, it has been reported thatA19-144 blocked the Aβ₂₅₋₃₅-induced P-Akt decrease and P-GSK-3βincrease, indicating activation of the P13K neuroprotective pathway(Lahmy et al., Neuropsychopharmacology, 2013). In the dose-range tested,A19-144 attenuated the hyperphosphorylation of Tau on physiologicalepitopes (AT-8 antibody clone) and on pathological epitopes (AT-100clone). ANAVEX2-73 also has been reported decreasing the Aβ₂₅₋₃₅-inducedendogenous Aβ₁₋₄₂ seeding.

A series of aminotetrahydrofuran compounds have been reported asexhibiting anti-amnesic, anticonvulsant, antidepressant andneuroprotective activities.¹⁻⁴ Among them,tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride(ANAVEX2-73) is a mixed muscarinic/σ₁ protein profile, but with betterselectivity for the σ₁ subtype as compared with σ₂ sites.¹ Reportedbinding analyses showed an IC₅₀=860 nM for σ₁ and no affinity for σ₂sites. Moreover, the screening profile showed micromolar affinities formuscarinic M1-M4 receptors (IC₅₀=3.3-5.2 μM), sodium channel site 2(IC₅₀=5.1 μM), and NMDA receptors (IC₅₀=8.0 μM).

Epilepsy is a chronic neurological disorder presenting a wide spectrumof diseases that affect approximately 50 million people worldwide.Neuronal activity is a prerequisite for proper brain function. However,disturbing the excitatory—inhibitory equilibrium of neuronal activitymay induce epileptic seizures. These epileptic seizures can be groupedinto two basic categories of (i) partial, and (ii) generalized. Withoutbeing bound by any particular theory, partial seizures originate inspecific brain regions and remain localized—most commonly the temporallobes (containing the hippocampus), whereas generalized seizures appearin the entire forebrain as a secondary generalization of a partialseizure. The International League Against Epilepsy further classifiedpartial seizures, separating them into simple and complex, depending onthe presence or the impairment of a consciousness state (Dreifuss etal., 1981). The league also categorized generalized seizures intonumerous clinical seizure types, some examples of which are outlinedbelow:

“Absence seizures” occur frequently, having a sudden onset andinterruption of ongoing activities. Additionally, speech is slowed orimpeded with seizures lasting only a few seconds;

“Tonic-clonic seizures,” often known as “grand mal”, are the mostfrequently encountered of the generalized seizures (Dreifuss et al.,1981). This generalized seizure type has two stages: tonic musclecontractions which then give way to a clonic stage of convulsivemovements. The patient remains unconscious throughout the seizure andfor a variable period of time afterwards; and,

“Atonic seizures,” known as “drop attacks”, are the result of suddenloss of muscle tone to either a specific muscle, muscle group or allmuscles in the body.

Reference is also made to other antiepileptic drugs. Note is made ofAcetazolamide; Benzodiazepines (e.g., Clonazepam/Klonopin®,Clorazepate/Tranxene®, diazepam/Valium®, lorazepam/Ativan®, midazolam);Carbamazepine (Tegretol®/Carbatrol®); Chlordiazepoxide; Clobazam;Cortiosteroids; Eslicarbazepine/Eslicarbazepine acetate; Ethosuximide(Zarontin®); Ethotoin; Felbamate; Lacosamide (Vimpat®); Lamotrigine(Lamictal®); Levetiracetam (Keppra®); Mephyntoin; Mephobarbitol;Methsuxamide; Oxcarbazepine (Trileptal®); Paramethadione; Perampanel(Fycompa); Phenacemide; Phenobarbital; Phensuxamide; Phenytoin(Dilantin®); Pregabalin (Lyrica®); Primidone (Mysoline®); Progabide;Rufinamide; Stiripentol; Sulthiame; Tiagabine (Gabitril®); Topiramate(e.g., Topamax®); Tremethadione; Valproate (Depakote®); Vigabatrin; and,Zonisamide (Zonegram®).

For convenience, these drugs as well as donepezil, memantine,galantamine, and ribastigimine will be collectively referred to as“anti-epilepsy drugs” or “AED's.”

Reference is made to the following publications, the teachings of whichare incorporated by reference in their entirety as are all documentscited herein.

1. Vamvakides (2002) Ann Pharm Fr 60:88-92;

2. Vamvakides (2002) Ann Pharm Fr 60:415-22;

3. Espallergues et al. (2007) Br J Pharmacol 152:267-79;

4. Villard et al (2009) Neuropsychopharmacology 34:1552-66;

5. Maurice et al. (1996) Brain Res 706:181-93;

6. Zussy et al. (2011)Am J Pathol 179:315-34;

7. Hayashi & Su (2007) Cell 131:596-610.;

8. Su et al. (2010) Trends Pharmacol Sci 31:557-566;

9. Meunier et al. (2006) Br J Pharmacol 149:998-1012.

10. European Patent Application No. 08 702 158.0, “New Sigma-ReceptorLigands with Anti-Apoptotic and/or Pro-Apoptotic Properties OverCellular Biochemical Mechanisms, With Neuroprotective, Anti-Cancer,Anti-Metastic and Anti-(Chronic) Inflammatory Action (also, U.S. Ser.No. 12/522,761).

11. U.S. Ser. No. 13/201,271, “Sigma(S)-Receptor Ligands WithAnti-Apoptotic and/or Pro-Apoptotic Properties.”

12. Dovey et al., Functional gamma-secretase inhibitors reducebeta-amyloid peptide levels in brain, J Neurochem. 2001 January;76(1):173-81

13. Motamedi, G K et al., “Antiepileptic drugs and memory. EpilepsyBehay. 2004 August; 5(4):435-9.

14. Michelle Price et al.,“Antiepileptic drugs for the primary andsecondary prevention of seizures after intracranial venous thrombosis,”Intervention Review, Cochrane Epilepsy Group Published Online: 2 AUG.2014, Assessed as up-to-date: 12 AUG. 2013, DOI:10.1002/14651858.CD005501.pub3

15. Vajda F J et al.,“The efficacy of the newer antiepileptic drugs incontrolling seizures in pregnancy,” Epilepsia. 2014 August;55(8):1229-34. doi: 10.1111/epi.12711. Epub 2014 Jul. 3.

16. Smith, B N, “Prophylaxis for post-traumatic epilepsy: can yourkinase do that?, “Epilepsy Curr. 2014 January; 14(1):38-40. doi:10.5698/1535-7597-14.1.38.

17. Sykes L et al., “Antiepileptic drugs for the primary and secondaryprevention of seizures after stroke,” Cochrane Database Syst Rev. 2014Jan. 24; 1:CD005398. doi: 10.1002/14651858.CD005398.pub3.

18. Baslow M H, “N-acetylaspartate in the vertebrate brain: metabolismand function,” Neurochem Res. 2003 June; 28(6):941-53.

SUMMARY OF THE INVENTION

Structure 1 has the systematic name1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride.

Structure 2 has the systematic name1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanaminehydrochloride.

The invention concerns dosages form comprising a therapeuticallyeffective amount of A19-144 and A2-73 and a therapeutically effectiveanti-seizure amount of at least one AED. For convenience A19-144 andA2-73 will, at times, be collectively referred to herein as “A19/2.”

It is a particular advantage of the combination of A19/2 and AED isthat, in combination with A19-144 or A2-73, sub-MED doses of AED aretherapeutically effective. AED's are implicated in memory loss insubjects taking AED's. Lower AED doses result is absent or lessenedmemory loss or memory impairment.

In some embodiments, the AED is donepezil, with reference to donepezilat from about 0.5 mg to about 23 mg, and particularly from about 0.5 mgto less than about 5 mg, and more particularly from about 1 to about 3.5mg. With the synergistic effect in combination with A19-144 or A2-73,doses below 0.5 mg are effective.

In other embodiments the AED is galantamine, and particularly from about0.5 mg to about 20 mg. With the synergistic effect in combination withA19/2 doses below 8 mg/day are therapeutically effective. Particularnote is made of dosing at 6 mg/day. Doses are usefully delivered inabout 2 doses.

Attention is drawn to a dosage form wherein said AED is rivastagmine,and particularly from about 0.5 mg to about 20 mg. With the synergisticeffect in combination with A19/2, doses below 3 mg/day aretherapeutically effective. Particular note is made of dosing at 2mg/day. Doses are usefully delivered in about 2 doses (morning andevening).

Further attention is drawn to the dosage form an AED is memantine, withparticular reference to an anti-seizure amount of from about 0.5 mg toabout 30 mg. With the synergistic effect in combination with A19/2,doses below 0.5 mg/day are therapeutically effective. Particular note ismade of dosing at 0.4 mg/day.

This invention further includes a therapeutic method of anti-seizuretherapy in a subject exhibiting seizure activity with particularreference to epilepsy. Comprising a therapeutically effective dose ofA19/2 in conjunction with a therapeutically effective dose of at leastone AED. Note is further made of co-timely administration of saidtherapeutically effective amount of A19-144 in conjunction with atherapeutically effective amount of at least one AED dose selected fromthe group consisting of Acetazolamide; Benzodiazepines (e.g.,Clonazepam/Klonopin®, Clorazepate/Tranxene®, diazepam/Valium®,lorazepam/Ativan®, midazolam); Carbamazepine (Tegretol®/Carbatrol®);Chlordiazepoxide; Clobazam; Cortiosteroids;Eslicarbazepine/Eskucarbazepine acetate; Ethosuximide (Zarontin®);Ethotoin; Felbamate; Lacosamide (Vimpat®); Lamotrigine (Lamictal®);Levetiracetam (Keppra®); Mephyntoin; Mephobarbitol; Methsuxamide;Oxcarbazepine (Trileptal®); Paramethadione; Perampanel (Fycompa);Phenacemide; Phenobarbital; Phensuxamide; Phenytoin (Dilantin®);Pregabalin (Lyrica®); Primidone (Mysoline®); Progabide; Rufinamide;Stiripentol; Sulthiame; Tiagabine (Gabitril®); Topiramate (e.g.,Topamax®); Tremethadione; Valproate (Depakote®); Vigabatrin; and,Zonisamide (Zonegram®) as well as donepezil, memantine, galantamine, andrivastigmine. Particular reference is made to donepezil dosed at fromabout 0.5 mg to about 23 mg, and particularly from about 0.5 mg to lessthan about 5 mg, and more particularly from about 1 to about 3.5 mg.

Note is made of the following sub-MED doses—

-   Acetazolamide, less than about 8 mg/kg/day;-   Clonazepam/Klonopin®, less than about 1.5 mg/day for adults and for    children up to 10 years of age or 30 kg of body weight, doses of    less than about 0.01 mg/kg/day;-   Clorazepate/Tranxene®, less than about 30 (mg);-   Lorazepam/Ativan®, less than about 0.1 mg/kg;-   Midazolam (intranasal midazolam in children) less than about 0.2    mg/kg;-   Carbamazepine (Tegretol®/Carbatrol®), less than about 7.5 mg/day;-   Diazepam/Valium®, less than about 0.2 mg/kg;-   Chlordiazepoxide, less than about 30 mg/day;-   Clobazam, for body weight 30 kg or less, less than about 5 mg/day    and for body weight-   30 kg or more, less than about 10 mg/day;-   Hydrocortisone, less than about 5 mg/kg/day;-   Eslicarbazepine/Eslicarbazepine acetate, less than about 800 mg/day;-   Ethosuximide (Zarontin®), less than about 250 mg daily every 4-7    days;-   Ethotoin, less than about 2 g daily;-   Felbamate, for adults, less than about 1200 mg/day, for children    2-14 yrs, less than about15 mg/kg/day;-   Lacosamide (Vimpat®), less than about 50 mg twice daily.-   Lamotrigine (Lamictal®), less than about 25 mg/day;-   Levetiracetam (Keppra®); less than about 1000 mg/day;-   Mephyntoin, less than about 200 mg/day;-   Mephobarbitol; less than about 400 mg/day;-   Methsuxamide, less than about 250 mg daily every 4-7 days;-   Oxcarbazepine (Trileptal®); less than about 600 mg/day;-   Paramethadione; less than about 150 mg/day;-   Perampanel (Fycompa), less than about 2 mg/day;-   Phenacemide, less than about 500 milligrams three times a day;-   Phenobarbital, establish a serum level of less than about10 μg/mL;-   Phensuxamide, less than about 0.5 g b.i.d;-   Phenytoin (Dilantin®), less than about 100 mg a day;-   Pregabalin (Lyrica®), less than about 75 mg 2 times a day;-   Primidone (Mysoline®); a dose of less than about 10 mg/kg/day;-   Progabide, daily dose of less than about 2100 mg;-   Rufinamide, less than about 400 mg/day;-   Stiripentol, less than about 250 mg twice a day;-   Sulthiame, less than about 100 mg/day;-   Tiagabine (Gabitril®), less than about 4 mg/day;-   Topiramate (e.g., Topamax®), less than about 25 mg/day;-   Tremethadione, less than about 900 mg/day;-   Valproate (Depakote®), less than about 10 mg/kg-   Vigabatrin; less than about 50 mg/kg/day and,-   Zonisamide (Zonegram®), less than about 100 mg once a day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows main metabolite ANAVEX19-144: Mean C_(max) values and meanterminal elimination half-life t_(1/2) of AV19-144 show a dose dependentincrease across the 10 to 60 mg AV2-73 dose steps (with the exception ofthe 40 mg step) and ranged from 1.31 to 22.28 ng/ml and 8.56 hours to28.74 hours, respectively.

FIG. 2 shows the mean residence time of AV19-144 shows a dose-dependentincrease ranging from 14.27 hours after 10 mg to 42.68 hours after 60 mgAV2-73.

DETAILED DESCRIPTION OF THE INVENTION

This invention will be better understood with reference to the followingdefinitions:

-   A. “Therapeutically effective amount” as to a drug dosage, shall    mean that dosage that provides the specific pharmacological response    for which the drug is administered in a significant number of    subjects in need of such treatment. Here, the desired    pharmacological response is a reduction in the number of seizures    experienced by a subject. Seizures, their origin and management are    subject to a variety of variables. Thus reference to “specific    pharmacological response for which the drug is administered in a    significant number of subjects in need of such treatment” is a    recognition that a “therapeutically effective amount,” administered    to a particular subject in a particular instance will not abort    every seizure onset, even though such dosage is deemed a    “therapeutically effective amount” by those skilled in the art. It    is to be further understood that drug dosages are, in particular    instances, measured as oral dosages, or parenteral or inhaled    dosages or with reference to drug levels as measured in blood.

Therapeutically effective amounts of A19-144 and A2-73 include 0.01-100mg/daily, preferably 0.5-10 mg/daily, more preferably 0.5-2.0 mg/daily.Dosing once every two days (3 times a week) is noted.

-   B. “Co-timely” as to drug administration shall mean administration    of a second drug while a first drug for is present in a    therapeutically effective amount. It is to be understood that in    some instances this will require sequential administration. In some    instances, multiple routes of administration will be employed such    as intravenous or subcutaneous injection.-   C. “Coordinated” in the practice of the present invention of    combining A19/2 administration with AED administration shall mean    administration of at least one AED such that effective plasma levels    of the AED will be present in a subject generally coincident with a    therapeutically effective amount of A19/2. The coordination time is    necessarily related to the route of AED administration. That is, for    example, i.m. routes will generally have shorter lead times to peak    plasma level than oral routes. In some embodiments this will be    about 0.5 to about 12 hours after A19-144 or A2-73 has been    administered.-   D. “Unit dosage form” shall mean single drug administration entity.    By way of example, a single tablet, capsule, dragee, or trochee,    suppository, or syringe combining both A19-144 or A2-73 and at least    one AED are examples of unit dosage forms.-   E. “Enhanced therapeutic effect” in the context of this invention    shall mean that relief from seizures (an increased latency period)    with a disclose combination of A19-144 or A2-73 with at least one    AED compared to the same doses of each component given alone; or    that dose of one or both component(s) below what would otherwise be    (apparently) a minimum effective dose (a “sub-MED”).-   F. As used herein, “prophylaxis” means complete absence of seizures    or lessening of seizure frequency by at least 20% and preferably 50%    and more preferably 80% as measured over the course of one year.

Without being bound by any particular theory it is believed that A19/2act as a disease-modifying or pathology-modifying agents not onlyprotecting brain cells from toxicity but also contributing to decreaseTau pathology and amyloid load. The pharmacokinetic data reveal a rapidand extensive biotransformation of AV2-73 to its main metaboliteAV19-144 after oral administration.

Disclosed herein is the administration schedule and combination ofA19-144 or A2-73 as a combination therapy with one or more AEDs.

A2-73 and metabolite AV19-144 were determined in plasma and urine usinga validated high performance liquid chromatographic method (HPLC) withtandem mass spectrometry. After separation from human plasma analyteswere injected into a LC-MS/MS. Quantification in plasma and urine wasconducted by an internal standard method (AV2-73) and a peak area ratiomethod (AV19-144). A weighted (1/x) regression 2^(nd) order wasperformed to determine the concentration of the analytes. The study wasconducted in accordance with the Principles of Good Laboratory Practice(GLP) as described under § 19, German Chemical Law. The validation basedon the EG-Dok. CPMP/ICH/381/95 and was reported according to“FDA-Guidance for Industry, Bioanalytical Method Validation” (May 2001).

The impact of administration schedule and combination of A19-144A withdonepezil or memantine is disclosed.

A19-144 was administered at 0.1 or 0.3 mg/kg ip once a day between day−7 and day −1 before Aβ₂₅₋₃₅ (day 0). It blocks the Aβ₂₅₋₃₅-inducedmemory deficits (spontaneous alternation in the Y maze and passiveavoidance response) and lipid peroxidation in the hippocampus 7 daysafter Aβ₂₅₋₃₅. A19-144 (0.3 mg/kg ip) is also effective whenadministered once a day between day 7 and day 13 after Aβ₂₅₋₃₅ (on day0), on memory deficits and lipid peroxidation increase measured 14 daysafter Aβ₂₅₋₃₅.

Both A19-144 and A2-73 are believed effective in preventing ormoderating the peptide, Aβ₂₅₋₃₅,-induced toxicity and learningimpairments when it is injected during one week before the peptide.Post-peptide administration is not required. Without being bound by anyparticular theory, this pre-insult protection schedule triggersneuromodulatory mechanisms (believed to impact the muscarinic and σ₁receptors) to therapeutically protect the brain from amyloid toxicity.Chronic activation of the σ₁ receptor has been shown to facilitate ERstress response and modify lipid rafts composition, sustaining long-termmodifications in the cell physiology.^(7,8)

A19-144 is able to reverse the Aβ₂₅₋₃₅-induced toxicity and learningimpairments when it is injected repeatedly one week after the peptide.This is a restorative effect of the compound, together with a delayedability to reduce the toxic load in the brain. Without being bound byany particular theory, the protective pathways activated by muscarinicreceptor (involving the PI3K/AKT and MAPK pathways), modulated by the σ₁receptor activation are likely to be involved in these effects.

The anti-amnesic and neuroprotective effect of A19-144 and A2-73 againstamyloid toxicity is effective in pre- and post-protection, meaning whenthe drug is administered before or after the amyloid peptide challenge,and the combination with donepezil boosts the therapeutic efficacy ofeach drug. A19-144 and A2-73 in combination with each of valproate,ethosuximide and gabapentin are also effective.

EXAMPLE 1 Seizure Prophylaxis: A19-144

A 13 year old male is experiencing 4 to 7 seizures per day with abaseline of 6.6 seizures per day. A19-144 is administered daily at 2.0mg for 5 days. Seizures reduce to 2.2 per day for 8 weeks post dosing.

EXAMPLE 2 Seizure Prophylaxis: A19-144 and Donepezil

The 13 year old male of example 1 is experiencing seizures at 2.2 perday at 6 months post dosing as stated in Example 1. The subject isadministered low dose donepezil (4 mg daily) for 5 days cotimely withcontinued A19-144 administration daily at 2.0 mg for 5 days. No seizuresare detected at 6 months post dosing. Cognitive testing detects nodiminution of memory as compared with the subject prior to donepeziladministration.

EXAMPLE 3 Seizure Prophylaxis: A19-144

A 57 year old female is experiencing 6 to 8 seizures per day with abaseline of 6.6 seizures per day. A19-144 is administered daily at 2.0mg for 5 days. Seizures reduce to 1.2 per day for 8 weeks post dosing.

EXAMPLE 4 Seizure Prophylaxis: A19-144 and Eslicarbazepine Acetate

The 57 year old female of Example 3 is experiencing an average of 1.2seizures per day at 6 months post dosing as stated in Example 3. Thesubject is administered low dose Eslicarbazepine acetate at 600 mg/day;for 5 days cotimely with continued A19-144 administration daily at 2.0mg for 5 days. No seizures are detected at 6 months post dosing.Cognitive testing detects no diminution of memory as compared with thesubject prior to Eslicarbazepine acetate administration.

EXAMPLE 5 Seizure Prophylaxis: A19-144 and Lacosamide

A 10 year old female is experiencing seizures 3.2 per day. The subjectis administered lacosamide at 60 mg two times per day for 5 days andcotimely administration of A19-144 daily at 2.0 mg for 5 days. Noseizures are detected at 6 months post dosing.

EXAMPLE 6 Seizure Prophylaxis: A19-144 and Levetiracetam

The 9 year old female is experiencing an average of 3.3 seizures perday. The subject is administered Levetiracetam at 400 mg two times perday for 5 days and cotimely administration of 3.0 mg of A19-144 dailyfor 5 days. No seizures are detected at 6 months post dosing. Cognitivetesting detects no diminution of memory as compared with the subjectprior to Levetiracetam administration.

The results of Examples 1 through 6 above are similarly effective whenA2-73 is substituted for A19-144.

Dosing Information/Dosage Forms:

For Anavex19-144and for A2-73, dosages of about 0.01-100 mg/daily,preferably 0.5-10 mg/daily, more preferably 0.5-2 mg/daily. Dosing onceevery two days (3 times a week) is noted. AD is a chronic disease, sostaring treatment promptly with diagnosis is preferred. For dosages ofdonepezil, galantamine, rivastigmine, and memantinedonepezil,galantamine, rivastigmine is used advantageously in combination withA19-144 or with A2-73. In some embodiments, these may be administered insub-MED doses.

Particular attention is drawn to the method of this invention comprisingA19-144 and A2-73 administration combined with administration of atleast one AED, wherein at least one of said therapeutically effectiveamounts of either A19-144 or A2-73 and the AED sub-therapeutic (sub-MED)as compared to the active dose when used alone. In the practice of thisinvention, either the A19/2 dose or the AED dose is used in sub-MEDamount or both are. While this does not exclude more than one AED beingused in treatment of a single subject, it is contemplated thatparticular embodiments will consist of A19-144 or A2-73 and an AED,wherein one or both drugs are administered in sub-MED amounts.Non-limiting useful doses for A19-144 or A2-73 in combination therapyare as follows:

-   Donepezil 1-3 mg/day or 5 mg once every two days; Rivastigmine 1    mg/day;-   Galantamine 8-10 mg/day once a day; and Memantine 1-5 mg/day.

Attention is drawn to dosages of donepezil of 5 mg or 10 mg administeredorally once per day. Dosages up to about 23 mg/day are also noted.

Reported dosages of galantamine are about 8 to 16 mg twice daily. Noteis made of dosage range from about 0.5 to about 8 mg, and optionallyfrom about 1 to about 6 mg.

Reported rivastigamine dosages begin with about 1.5 mg orally twice aday with morning and evening meals. In some embodiments, after about twoweeks of treatment, the rivastagmine dosage is increased to about 3 mgtwice a day. Subsequent increases to 4.5 mg and 6 mg twice a day arenoted. Rivastagmine is notably useful in transdermal patch form. Auseful initial patch dose: 4.6 mg/24 hours, but a range of 1-8 mg isnoted. In some embodiments a maintenance patch dose after about fourweeks of treatment is increased from about 8-16 mg, and particularly,9.5 mg/24 hours for as long as this dose is beneficial. The dose canthen be increased to about 9-20 mg and particularly about 13.3 mg/24hours.

Useful memantine dosing is initial about 5 mg orally once daily, thentitrated upwards by 5 mg per week. Useful maintenance dosing is 5 mgonce daily up to 10 mg twice daily are noted. Useful doses are fromabout 0.5 to about 20 mg, and lower (sub-MED) doses are contemplated.

Dosing for donepezil, galantamine, rivastigmine, or memantine may bedaily, but further include from twice daily to every other day, to onceper week or less frequently. Of course, transdermal dosing is also acontinuous dosing.

The pharmacologically active compositions of this invention can beprocessed in accordance with conventional methods of Galenic pharmacy toproduce medicinal agents for administration to subjects, e.g., mammalsincluding humans.

The compositions of this invention individually or in combination areemployed in admixture with conventional excipients, i.e.,pharmaceutically acceptable organic or inorganic carrier substancessuitable for parenteral, enteral (e.g., oral or inhalation) or topicalapplication which do not deleteriously react with the activecompositions. Suitable pharmaceutically acceptable carriers include butare not limited to water, salt solutions, alcohols, gum arabic,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, titanium dioxide, silicic acid, viscous paraffin, perfume oil,fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.The pharmaceutical preparations can be sterilized and if desired mixedwith auxiliary agents, e.g., lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, flavoring and/or aromatic substances and the likewhich do not deleteriously react with the active compositions. They canalso be combined where desired with other active agents, e.g., vitamins.

In some embodiments of the present invention, dosage forms includeinstructions for the use of such compositions.

For parenteral application, particularly suitable are injectable,sterile solutions, preferably oily or aqueous solutions, as well assuspensions, emulsions, or implants, including suppositories. Ampules,vials, and injector cartridges are convenient unit dosages.

Also for parenteral application, particularly suitable are tablets,dragees, liquids, drops, suppositories, or capsules. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed. Sublingualand buccal forms are also noted.

Sustained or directed release compositions can be formulated, e.g.,liposomes or those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc. It is also possible to freeze-dry the newcompositions and use the lyophilizates obtained, for example, for thepreparation of products for injection.

Generally, the compositions of this invention are dispensed in unitdosage form comprising A19-144 or A2-73 at about 1 to about 100 mg and0.5 to 5 mg of donepezil or AED in a pharmaceutically acceptable carrierper unit dosage.

The invention claimed is:
 1. A dosage form comprising a therapeuticallyeffective amount of an anti-seizure drug selected from A19-144 and acombination of A19-144 and A2-73, and a sub-MED amount of at least oneanti-epilepsy drug (AED), wherein the sub-MED dose and the at least oneAED are selected from the group consisting of: less than about 8 mg/dayof acetazolamide; less than about 1.5 mg/day of Clonazepam for an adult,less than about 0.01 mg/kg/day of Clonezepam for a child up to 10 yearsof age or 30 kg of body weight; less than about 30 (mg) of Clorazepate;less than about 0.1 mg/kg of Lorazepam; less than about 0.2 mg/kg ofMidazolam; less than about 7.5 mg/day of Carbamazepine; less than about0.2 mg/kg of Diazepam; less than about 30 mg/day of Chlordiazepoxide;less than about 5 mg/day for body weight 30 kg or less, and less thanabout 10 mg/day for body weight 30 kg or more, of Clobazam; less thanabout 5 mg/kg/day of Hydrocortisone; less than about 800 mg/day ofEslicarbazepine/Eslicarbazepine acetate; less than about 250 mg dailyevery 4-7 days of Ethosuximide; less than about 2 g daily of Ethotoin;less than about 1200 mg/day for adults, for children 2-14 yrs, less thanabout 15 mg/kg/day of Felbamate; less than about 50 mg twice daily ofLacosamide; less than about 25 mg/day of Lamotrigine; less than about1000 mg/day of Levetiracetam; less than about 200 mg/day of Mephyntoin;less than about 400 mg/day of Mephobarbitol; less than about 250 mgdaily every 4-7 days of Methsuxamide; less than about 600 mg/day ofOxcarbazepine; less than about 150 mg/day of Paramethadione; less thanabout 2 mg/day of Perampanel (Fycompa); less than about 500 milligramsthree times a day of Phenacemide; establish a serum level of less thanabout 10 μg/mL of Phenobarbital; less than about 0.5 g b.i.d ofPhensuxamide; less than about 100 mg a day of Phenytoin; less than about75 mg 2 times a day of Pregabalin; a dose of less than about 10mg/kg/day of Primidone; daily dose of less than about 2100 mg ofProgabide; less than about 400 mg/day of Rufinamide; less than about 250mg twice a day of Stiripentol; less than about 100 mg/day of Sulthiame;less than about 4 mg/day of Tiagabine; less than about 25 mg/day ofTopiramate; less than about 900 mg/day of Tremethadione; less than about10 mg/kg of Valproate; less than about 50 mg/kg/day of Vigabatrin and,less than about 100 mg once a day of Zonisamide.
 2. The dosage form ofclaim 1 wherein the therapeutically effective amount of A19-144 or ofA19-144 and A2-73 in combination is from about 0.01 to about 100mg/daily.
 3. The dosage form of claim 1 wherein said dosage form is aunit dosage form.
 4. A method of treating seizures in a subject in needof such treatment comprising administering an therapeutically effectiveamount of A19-144 or a combination of A19-144 and A2-73 in conjunctionwith a sub-MED amount of an AED, wherein the sub-MED dose and the atleast one AED are selected from the group consisting of: less than about8 mg/day of acetazolamide; less than about 1.5 mg/day of Clonazepam foran adult, less than about 0.01 mg/kg/day of Clonezepam for a child up to10 years of age or 30 kg of body weight; less than about 30 (mg) ofClorazepate; less than about 0.1 mg/kg of Lorazepam; less than about 0.2mg/kg of Midazolam; less than about 7.5 mg/day of Carbamazepine; lessthan about 0.2 mg/kg of Diazepam; less than about 30 mg/day ofChlordiazepoxide; less than about 5 mg/day for body weight 30 kg orless, and less than about 10 mg/day for body weight 30 kg or more, ofClobazam; less than about 5 mg/kg/day of Hydrocortisone; less than about800 mg/day of Eslicarbazepine/Eslicarbazepine acetate; less than about250 mg daily every 4-7 days of Ethosuximide; less than about 2 g dailyof Ethotoin; less than about 1200 mg/day for adults, for children 2-14yrs, less than about 15mg/kg/day of Felbamate; less than about 50 mgtwice daily of Lacosamide; less than about 25 mg/day of Lamotrigine;less than about 1000 mg/day of Levetiracetam; less than about 200 mg/dayof Mephyntoin; less than about 400 mg/day of Mephobarbitol; less thanabout 250 mg daily every 4-7 days of Methsuxamide; less than about 600mg/day of Oxcarbazepine; less than about 150 mg/day of Paramethadione;less than about 2 mg/day of Perampanel (Fycompa); less than about 500milligrams three times a day of Phenacemide; establish a serum level ofless than about 10 μg/mL of Phenobarbital; less than about 0.5 g b.i.dof Phensuxamide; less than about 100 mg a day of Phenytoin; less thanabout 75 mg 2 times a day of Pregabalin; a dose of less than about 10mg/kg/day of Primidone; daily dose of less than about 2100 mg ofProgabide; less than about 400 mg/day of Rufinamide; less than about 250mg twice a day of Stiripentol; less than about 100 mg/day of Sulthiame;less than about 4 mg/day of Tiagabine; less than about 25 mg/day ofTopiramate; less than about 900 mg/day of Tremethadione; less than about10 mg/kg of Valproate; less than about 50 mg/kg/day of Vigabatrin and,less than about 100 mg once a day of Zonisamide.
 5. The method of claim4 wherein said administering of A19-144 or the combination of A19-144and A2-73 in conjunction with a sub-MED amount of an AED is co-timely.6. The method of claim 4 wherein said administering of A19-144 or thecombination of A19-144 and A2-73 in conjunction with a sub-MED amount ofan AED is coordinated.